Tranexamic acid rapidly inhibits fibrinolysis, yet transiently enhances plasmin generation in vivo.

Abstract

Tranexamic acid (TXA) is a lysine analogue that inhibits plasmin generation and has been used for decades as an antifibrinolytic agent to reduce bleeding. Recent reports have indicated that TXA can paradoxically promote plasmin generation. Blood was obtained from 41 cardiac surgical patients randomly assigned to TXA or placebo before start of surgery (preOP), at the end of surgery (EOS), then again on postoperative day 1 (POD-1) as well as POD-3. Plasma levels of tissue-type plasminogen activator (t-PA), urokinase (u-PA), the plasmin-antiplasmin (PAP) complex, as well as t-PA and u-PA-induced clot lysis assays were then determined. Clot lysis and PAP complex levels were also assessed in healthy volunteers before and at various time points after taking 1 g TXA orally. Surgery induced an increase in circulating t-PA, yet not u-PA at EOS. t-PA levels were unaffected by TXA; however, u-PA levels were significantly reduced in patients on POD-3. t-PA and u-PA-induced clot lysis were both inhibited in plasma from TXA-treated patients. In contrast, PAP complex formation, representing plasmin generation, was unexpectedly enhanced in the plasma of patients administered TXA at the EOS time point. In healthy volunteers, oral TXA effectively blocked fibrinolysis within 30 min and blockade was sustained for 8 h. However, TXA also increased PAP levels in volunteers 4 h after administration. Our findings demonstrate that TXA can actually augment PAP complex formation, consistent with an increase in plasmin generation in vivo despite the fact that it blocks fibrinolysis within 30 min. This may have unanticipated consequences in vivo.

• Authors: Dominik F Draxler, Saffanah Zahra, Isaac Goncalves, Huyen Tran, Gryselda Hanafi, Heidi Ho, Charithani B Keragala, Anton Ilich, Nigel S Key, Paul S Myles, Robert L Medcalf
• Journal: Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis (Blood Coagul Fibrinolysis) Vol. 32 Issue 3 Pg. 172-179 (Apr 01 2021) ISSN: 1473-5733 [Electronic] England
• PMID: 33443933 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial)
• Copyright: Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.

Chemical References

• Antifibrinolytic Agents
• alpha-2-Antiplasmin
• plasmin-plasmin inhibitor complex
• Tranexamic Acid
• PLAT protein, human
• Tissue Plasminogen Activator
• Fibrinolysin
• Urokinase-Type Plasminogen Activator

Topics

• Aged
• Antifibrinolytic Agents (pharmacology, therapeutic use)
• Female
• Fibrinolysin (analysis, metabolism)
• Fibrinolysis (drug effects)
• Humans
• Male
• Middle Aged
• Postoperative Period
• Preoperative Period
• Tissue Plasminogen Activator (blood)
• Tranexamic Acid (pharmacology, therapeutic use)
• Urokinase-Type Plasminogen Activator (blood)
• alpha-2-Antiplasmin (analysis, metabolism)